PROJECT SUMMARY This proposal presents a five-year research career development program focused on the translation of oncolytic modified poliovirus (PVSRIPO) into a novel treatment for patients with advanced melanoma. The candidate is currently an Assistant Professor of Surgery at Duke University. The candidate has previous research and clinical experience in the management of patients with advanced melanoma and has now chosen to focus on immunology-driven approaches with a mentor who is an accomplished immunologist, Smita Nair, PhD. The proposed experiments and didactic work will provide the candidate with a unique set of immunologic and laboratory skills that will enable her transition to independence as a physician scientist in the field of melanoma therapeutics. Melanoma has been dramatically increasing in incidence for the last 30 years and is the most common fatal skin malignancy. Programmed death protein 1 (PD-1) antagonists represent important recent advances in the care of patients with metastatic melanoma. However, 60% of patients fail to respond to PD-1 therapy and late resistance remains a problem. Oncolytic virotherapy has emerged as a promising treatment for advanced melanoma due to its ability to elicit anti-neoplastic effects stemming from combined direct viral cytotoxicity and innate antiviral activation. PVSRIPO, the live attenuated, serotype 1 poliovirus vaccine that was genetically modified to eliminate its neurovirulence, has shown unprecedented long-term survival in 20% of recurrent glioblastoma multiforme patients, otherwise a nearly uniformly fatal disease. Further development of PVSRIPO as treatment for advanced melanoma will fulfill a clinical need for more effective therapies for these patients. More specifically, the aims of this proposal are: 1) investigate PVSRIPO induced immune bioactivity in melanoma tumor tissue obtained from a Phase I trial of patients with advanced melanoma, 2) determine the efficacy of mouse PVSRIPO treatment, in conjunction with PD-1/PD-L1 blockade, on tumor growth in vivo, 3) determine PVSRIPO-mediated immune activation in vitro in a tumor explant model. The scientific objectives of this proposal are to 1) define how PVSRIPO treatment facilitates engagement of anti-tumor immune responses and 2) to determine if administration of mouse PVSRIPO with concurrent PD-1/PD-L1 antagonists will eliminate adaptive resistance and potentiate durable-anti-tumor responses.